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Brentuximab Vedotin and Nivolumab in Treating Participants With Early Stage Classic Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT03712202
Recruitment Status : Recruiting
First Posted : October 19, 2018
Last Update Posted : January 15, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This phase II trial studies how well brentuximab vedotin and nivolumab work in treating participants with stage I-II classic Hodgkin lymphoma. Monoclonal antibodies, such as brentuximab vedotin and nivolumab, may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Ann Arbor Stage I Hodgkin Lymphoma Ann Arbor Stage I Lymphocyte-Depleted Classic Hodgkin Lymphoma Ann Arbor Stage I Mixed Cellularity Classic Hodgkin Lymphoma Ann Arbor Stage I Nodular Sclerosis Classic Hodgkin Lymphoma Ann Arbor Stage IA Hodgkin Lymphoma Ann Arbor Stage IB Hodgkin Lymphoma Ann Arbor Stage II Hodgkin Lymphoma Ann Arbor Stage II Lymphocyte-Depleted Classic Hodgkin Lymphoma Ann Arbor Stage II Mixed Cellularity Classic Hodgkin Lymphoma Ann Arbor Stage II Nodular Sclerosis Classic Hodgkin Lymphoma Ann Arbor Stage IIA Hodgkin Lymphoma Ann Arbor Stage IIB Hodgkin Lymphoma Classic Hodgkin Lymphoma Lymphocyte-Rich Classic Hodgkin Lymphoma Drug: Bleomycin Drug: Brentuximab Vedotin Drug: Dacarbazine Drug: Doxorubicin Biological: Nivolumab Other: Quality-of-Life Assessment Drug: Vinblastine Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the 18 month progression free survival (PFS) for each arm of therapy stratified by positron emission tomography (PET)/computed tomography (CT)-2 response.

SECONDARY OBJECTIVES:

I. Assess safety, tolerability, and quality of life (QOL) for each arm of therapy.

II. Measure PET/CT-2 negativity rate after 2 lead-in cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD).

III. Evaluate the 3-year PFS and overall survival (OS) for each arm of treatment.

EXPLORATORY OBJECTIVES:

I. Evaluate if a baseline antitumor immune response, as assessed by a Nanostring gene panel, correlates with PFS.

II. Evaluate if minimal residual disease (MRD) status, as monitored by cancer personalized profiling by deep sequencing (CAPP-Seq) of circulating tumor (ct) deoxyribonucleic acid (DNA), can be correlated with PFS.

OUTLINE: Participants are assigned to 1 of 2 groups based on their PET/CT-2 scans.

GROUP I (PET/CT-2 NEGATIVE): Participants without bulky disease are randomized to either Arm A or B and participants with bulky disease are assigned to Arm B.

ARM A: Participants receive brentuximab vedotin intravenously (IV) over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeat every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Participants receive doxorubicin IV, bleomycin IV, vinblastine IV, dacarbazine IV on days 1 and 15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Participants then receive nivolumab IV over 60 minutes on day 1. Treatment with nivolumab repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

GROUP II (PET/CT-2 POSITIVE): Participants receive doxorubicin IV, vinblastine IV, dacarbazine, IV and brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants that are PET/CT negative receive nivolumab IV over 60 minutes on day 1. Treatment with nivolumab repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 264 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Front-Line PET/CT-2 Response-Adapted Brentuximab Vedotin and Nivolumab Incorporated and Radiation-Free Management of Early Stage Classical Hodgkin Lymphoma (cHL)
Actual Study Start Date : November 28, 2018
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Experimental: Group I Arm A (brentuximab vedotin, nivolumab)
Participants receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeat every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Group I Arm B (ABVD, nivolumab)
Participants receive doxorubicin IV, bleomycin IV, vinblastine IV, dacarbazine IV on days 1 and 15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Participants then receive nivolumab IV over 60 minutes on day 1. Treatment with nivolumab repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Bleomycin
Given IV
Other Names:
  • BLEO
  • BLM

Drug: Dacarbazine
Given IV
Other Names:
  • 4-(Dimethyltriazeno)imidazole-5-carboxamide
  • 5-(Dimethyltriazeno)imidazole-4-carboxamide
  • Asercit
  • Biocarbazine
  • Dacarbazina
  • Dacarbazina Almirall
  • Dacarbazine - DTIC
  • Dacatic
  • Dakarbazin
  • Deticene
  • Detimedac
  • DIC
  • Dimethyl (triazeno) imidazolecarboxamide
  • Dimethyl Triazeno Imidazol Carboxamide
  • Dimethyl Triazeno Imidazole Carboxamide
  • dimethyl-triazeno-imidazole carboxamide
  • Dimethyl-triazeno-imidazole-carboximide
  • DTIC
  • DTIC-Dome
  • Fauldetic
  • Imidazole Carboxamide
  • Imidazole Carboxamide Dimethyltriazeno
  • WR-139007

Drug: Doxorubicin
Given IV
Other Names:
  • Adriablastin
  • Hydroxyl Daunorubicin
  • Hydroxyldaunorubicin

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Drug: Vinblastine
Given IV
Other Names:
  • Vincaleucoblastine
  • VLB

Experimental: Group II (AVD, brentuximab vedotin, nivolumab)
Participants receive doxorubicin IV, vinblastine IV, dacarbazine, IV and brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants that are PET/CT negative receive nivolumab IV over 60 minutes on day 1. Treatment with nivolumab repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35

Drug: Dacarbazine
Given IV
Other Names:
  • 4-(Dimethyltriazeno)imidazole-5-carboxamide
  • 5-(Dimethyltriazeno)imidazole-4-carboxamide
  • Asercit
  • Biocarbazine
  • Dacarbazina
  • Dacarbazina Almirall
  • Dacarbazine - DTIC
  • Dacatic
  • Dakarbazin
  • Deticene
  • Detimedac
  • DIC
  • Dimethyl (triazeno) imidazolecarboxamide
  • Dimethyl Triazeno Imidazol Carboxamide
  • Dimethyl Triazeno Imidazole Carboxamide
  • dimethyl-triazeno-imidazole carboxamide
  • Dimethyl-triazeno-imidazole-carboximide
  • DTIC
  • DTIC-Dome
  • Fauldetic
  • Imidazole Carboxamide
  • Imidazole Carboxamide Dimethyltriazeno
  • WR-139007

Drug: Doxorubicin
Given IV
Other Names:
  • Adriablastin
  • Hydroxyl Daunorubicin
  • Hydroxyldaunorubicin

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Drug: Vinblastine
Given IV
Other Names:
  • Vincaleucoblastine
  • VLB




Primary Outcome Measures :
  1. 18-month Progression-free survival (PFS) for each arm of therapy [ Time Frame: Up to 18 months ]
    Will be estimated using the method of Kaplan and Meier.


Secondary Outcome Measures :
  1. Incidence of adverse events evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 3 years ]
    Frequency tables will be used to summarize toxicity profile

  2. Scores from European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire C30, version 3 (EORTC-C30) for each arm of therapy [ Time Frame: Up to 3 years ]
    All of the scales range in score from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems.

  3. Positron emission tomography/computed tomography-2 negativity rate [ Time Frame: After 2 courses of ABVD (each course is 28 days) ]
  4. 3-year PFS for each arm of treatment [ Time Frame: Up to 3 years ]
    Will be estimated using the method of Kaplan and Meier.

  5. Overall survival for each arm of treatment [ Time Frame: Up to 3 years ]
    Will be estimated using the method of Kaplan and Meier.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Documented informed consent of the participant and/or legally authorized representative.

    • Assent, when appropriate, will be obtained per institutional guidelines.
  • Eastern Cooperative Oncology Group (ECOG) =< 2.
  • Histologically confirmed diagnosis of classical Hodgkin lymphoma (cHL) by current World Health Organization classification (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted, or classical Hodgkin lymphoma, NOS [not otherwise specified]) at local enrolling center.
  • Stage IA, IB, IIA, or IIB cHL by Cotswold modified Ann Arbor staging done prior to any treatment with ABVD.
  • Ability to document transverse diameter in cm of largest mediastinal mass and favorable versus unfavorable risk factor criteria as determined by German Hodgkin Study Group (GHSG) criteria at baseline prior to ABVD treatment.
  • Must have at baseline prior to ABVD treatment at least one lesion that is > 1.5 cm in the longest diameter on cross-sectional imaging and measureable in two perpendicular dimensions on CT and fludeoxyglucose (FDG) avid by PET.
  • Absolute neutrophil count (ANC) >= 1,000/mm^3.
  • Platelets >= 75,000/mm^3.
  • Hemoglobin >= 8 g/dL.
  • Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless the elevation is known to be related to Gilbert's syndrome).
  • Aspartate aminotransferase (AST) =< 2.5 x ULN.
  • Alanine aminotransferase (ALT) =< 2.5 x ULN.
  • Creatinine clearance >= 30 mL/min per 24 hour urine collection or the Cockcroft-Gault formula.
  • Left ventricular ejection fraction (LVEF) >= 45%.
  • Carbon monoxide diffusion capacity (DLCO) (adjusted for hemoglobin [Hb]) >= 60%.
  • Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy.

    • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria:

  • Patients must be naive in terms of any prior therapy for Hodgkin lymphoma (including immunotherapy, chemotherapy or radiation therapy) with the exception that they may have received up to 2 cycles of ABVD as standard of care therapy prior to enrollment, as long as they can start subsequent therapy (therapy administered in Arms A, B1/B2, or C) within timelines specified by the trial.
  • Subjects with a non-lymphoma related condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drugs administration. Patients can have received short term dosing of steroids prior to the start of ABVD chemotherapy for management of symptoms of cHL and any steroids given for cHL symptom management should be tapered down to 10 mg or less of prednisone equivalents by the time of start of ABVD chemotherapy, and fully tapered off by week 1 of ABVD.
  • Sensory > grade 1 or any peripheral motor neuropathy.
  • History of another primary malignancy that has not been in remission for at least 3 years. (The following are exempt from the 3-year limit: nonmelanoma skin cancer, fully excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou [PAP] smear)
  • Known cerebral/meningeal disease.
  • History of progressive multifocal leukoencephalopathy (PML).
  • Known history of pancreatitis.
  • Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to their first dose of study drug(s).
  • Uncontrolled cardiac disease including ventricular dysfunction, left ventricular ejection fraction < 45%, coronary artery disease, or arrhythmias.
  • Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin, nivolumab, or any component of ABVD.
  • Known active infection with hepatitis B or hepatitis C. Patients who are hepatitis B carriers can enroll if have a negative hepatitis B polymerase chain reaction (PCR) DNA test and are on hepatitis B suppressive medication management with entecavir or lamivudine. Patients with past active hepatitis C virus (HCV) infection are eligible if they are PCR negative after curative therapy. Testing to be done only in patients suspected of having infections or exposures.
  • Known active infection with human immunodeficiency virus (HIV). Patients who are HIV positive can enroll if CD4 count is > 200/uL and have an undetectable HIV viral load within 28 days of enrollment, have concurrent management with infectious disease specialists, and are on stable combination antiretroviral therapy. Participants are required to be on antiretroviral regimens that are in accordance with the current International acquired immune deficiency syndrome (AIDS) Society guidelines concurrently with chemotherapy. The specific agents are at the discretion of the Investigator and the use of investigational agents currently available on an expanded access basis is allowed. Use of experimental antiretroviral agents or those containing zidovudine (including Combivir and Trizivir) or ritonavir (includes Norvir or Kaletra), Cobicistat, Didanosine (Videx or Videx EC), or similar potent CYP3 inhibitors are prohibited. In order to be eligible, participants taking zidovudine or ritonavir, Cobicistat, Didanosine, or other CYP3 inhibitors must change to a different regimen 7 days prior to therapy initiation. Changes to highly active antiretroviral therapy (HAART) therapy during the study may be made if medically necessary (toxicity, failure of regimen, etc.). Participants must be on HAART for at least 7 days prior to therapy.
  • Any active systemic viral, bacterial, or fungal infection requiring treatment with IV antimicrobial therapy within 1 week prior to enrollment.
  • Subjects with active interstitial pneumonitis.
  • Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Females only: pregnant or breastfeeding.
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03712202


  Show 30 Study Locations
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Alex Herrera, MD City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03712202     History of Changes
Other Study ID Numbers: 18157
NCI-2018-01592 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18157 ( Other Identifier: City of Hope Medical Center )
First Posted: October 19, 2018    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Lymphoma
Sclerosis
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoconjugates
Nivolumab
Antineoplastic Agents, Immunological
Doxorubicin
Liposomal doxorubicin
Bleomycin
Vinblastine
Dacarbazine
Imidazole
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action